The major objective of this research project is to investigate the molecular mechanism whereby the putative tumor suppressor gene deleted-in oral cancer-1 (doc-1) suppresses transformation phenotypes of malignant oral keratinocytes. Data will be presented to support the hypothesis that doc-1 exerts its effect on cancer cells by regulating their progression through the cell cycle in a manner that results in a significant increase in the accumulation of cells in the S phase. Detailed studies will be conducted to elucidate the role of doc-1 in the cell cycle. This application encompasses four specific aims: (1) to determine the pattern of expression of doc-1 in human tissues; 92) to determine the role of phosphorylation in the regulation of Doc-1 protein function; (3) to examine the role of doc-1 in the cell cycle; and (4) to identify the functional partners of Doc-1. The proposed studies will be conducted by a team of investigators active in the field of cell cycle and cancer research Close collaborations with the investigators conducting the other two research projects as well as with the Cell Culture and Tissue Bank and Pathology Cores will ensure that these two studies are validated at the clinical level.